Calreticulin (CALR) Mutation Screen in Myeloproliferative Neoplasms (MPNs)
Description
Somatic JAK2 V617F mutation is present in a majority (95%) of patients with Polycythaemia Vera (PV), but only in 50-60% of patients with Es-sential Thrombocythemia (ET) and Primary Myelofibrosis (PMF). Muta-tions in the gene encoding thrombopoietin receptor (MPL) exist in a small subset (5-10%) of patients with JAK2 V617F negative ET and PMF.
Recently, recurrent mutations in the gene encoding calreticulin (CALR) have been identified in a majority (70-85%) of MPN patients without JAK2 or MPL mutations. CALR mutations are never seen in PV and are always mutually exclusive to JAK2 and MPL mutations. These heterozygous mutations (insertions or deletions), located in exon 9, lead to a frameshift to a specific altered reading frame and result in a mutant protein with a novel C-terminal. ET and PMF patients with CALR mutations have lower haemoglobins, higher platelet counts, lower risk of thrombosis and a better overall survival than patients with mutated JAK2.
The causal relationship between CALR mutations and excessive platelet production is further supported by identification of these mutations in a proportion of RARS-T patients but not in MDS, AML or CML. Thus, CALR mutations are the second most frequent mutation after JAK2 in MPN's and impart a more indolent phenotype. CALR mutations are major driver events in the pathogenesis of MPN, occurring at the stem cell level and remain stable during disease evolution.
We suggest sequential testing on peripheral blood in order of mutation frequency for 1) JAK2, 2) CALR and 3) MPL, thereby improving the diagnostic accuracy of myeloproliferative neoplasms in the same way JAK2 testing has in the last decade.
Clinical details
Factors affecting results or interpretation: Samples received in heparin are not amenable to PCR based analysis and can therefore not be tested for JAK2 mutations.
Testing site
Synnovis : Genomics : King's College Hospital
Laboratory
SE-HMDS Laboratory for Molecular Haemato-Oncology
Sample type and volume required
5 mls peripheral blood or 1-2 mls Bone Marrow in 5 ml EDTA tube.
Special sample instructions
Please note: This test is not currently part of our accredited repertoire.
Storage and transport
First class postage is adequate but samples must be shipped with packaging appropriate for UN 3373 samples following packing instruction 650. See link below for further details: http://www.dft.gov.uk
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